Naaayoshi nagai



STATEd NAGAYOSHI NAGAI, or TOKYO-EU, JAPAN,

FRANCISCO, CALIFORNIA.

nssrenon 'ro M.

SYNTHETIC ANESTHET'IC AND rnocnss or MAKING SAME.

No Drawing.

'1 '0 all to 7mm it may concern:

Be it known that T, llaearosnrr Nauru, of No. 8 Aoyama ltiinami-machij Shichichome, Shibuya-machi, Toyotama-gun, Tokyo-fu, in the Empire of Japan, have in.- vented certain new and useful Improvements in and Relating to Synthetic Anesthetics and Processes of MakingSame; and I do hereby declare the following to be afull, clear, and exact description of the inven tion, such as will enable others skilled in the art to which it appertains to make and use the same. i 1 V This invention relates to the preparation of local anesthetic substances and particu larly to the synthesis of two new alkaloids which are hereinafter referred to as allocain S, (C H NO and allocain A (C H NO respectively. The object of the invention is to obtain by a novel, cheap, simple, chemical synthetic process such new alkaloids which are effective for the purpose of local anesthesis. a

The basis for the synthetic preparation of these two alkaloids is Inydriatin (C H NO) having the following constitutionz- Specif cation of Letters-Patent.

Patented Dec. 6, 1921 Application filed March za, 1916. Serial Noi 87,323.

the bromin of an excess of ethyl bromid which is added after the addition of water to d1ssolve the sulfate or chlorid of my driatin. Thismixture is digested in a vessel provided with a reflux cooler, forseveral hours over a water bath, at a temperature of 30-40 degrees oentigradew Mono-ethylmydriatin and diethlmydriatin are simultaneously formed in the digestion, accordmg to the equation I (Mydriatin) (Ethyl- Thus the vessel will contain a mixture of those mydriatin compounds aswell as a small quantity of unchanged mydriatin.

In order to separate the above products from one another, either ether free from alcohol, to dissolve the mixture of the basic substances mono-ethylrnydriatin, diethylmydriatin and unchanged mydriatin, is first added and then benzoyl chlorid is gradu- (Mono-ethyhmydrb atin-hydr0bromid) (Diethylmydriatinhydrobromid) DICK BUNNELL, or sAiv ally added to form benzoyl compounds of i the mono-ethyl and diethyl-mydriatin, or an etherial solution of ,benzoylchlorid is added to the mixture at once, and in either case c n uno n o o n mc no o 20 11 0001 +K2OO3 (Mono-ethyl mydriatin) (Diethyl mydriatin) (Benzoylmono-ethyl-mydriatin) The compounds thus prepared, namely, benzoylmonoethylmydriatin and benzoyl diethylmydriatin, may be administered as so prepared, that is, in combination or admixture or the etherial solution'may be separated from the alkaline liquid by means of a separating funnel. Dilute acid, hydrochloric acid being used in practice, is added gradually to the etherial solution which is (Benzoic chlorid) opa uogn oooo m on me na oooogm 2Ko1+ 00 H2O (Benzoyldiethyl-mydriatin=- allocain S) shaken vigorously and this process is continned until the watery layer in the mixture By separating the etherial solution from I 90 the wateryor dilute acid liquid bymeans of a separating funnel and completely evaporating the aqueous solution under reduced pressure, allocain S will be obtained as the hydrochlorid in the form of a colorless, transparent, vitreous mass. The constitution of allocain S is 2- Allocain A is obtained in a pure state from the residual etherial solution of the henzoyl compound of monoethylmydriatin by the following process. First, the ether is evaporated 0E and about 30% hydrochloric acid is added to the residue; the

(Benz0ylmono-ethyl-mydriatin) Then allocain A as hydrochlorid appears to shoot out in beautiful fiat crystalline needles, which when cooled will almost entirely separate themselves from the mother liquid. The constitution of allocain A is the following The crystals are collected from the mother liquor by filtering and are washed with acidi fied cold water to take away any impure salt which might remain. The crystals are then dissolved in a small quantity of warm water and, when they are brought down again by cooling, allocain hydrochlorid A in the purest state is obtained.

In the example of the process described above, ethyl bromid and benzoic chlorid are used, but it is naturally to be understood that the two :illocains can be produced by using other ethyl halids such as ethyl iodid instead of ethyl bromid, and benzoic anhydrid instead of its chlorid; but no special advantages can be obtained by such alternative method.

According to the experiments made in connection with this invention, the various derivatives of mydriatin, benzoyl derivatives of monoand di-alkyl and alkaryl, which term as here and hereinafter used, signifies either a group belonging to the aliphatic series or a group belonging to the aromatic series, mydriatin, benzoyl derivatives of latter is heated over a water bath until solid substances no longer appear even when cooled. Water is added to the solution. Then it becomes turbid owing to the separation of a small quantity of indifferent substances. and ether added to the filtrate in suflicient quantity to dissolve the remaining small quantity of the indifierent substances. The whole is shaken when these substances will dissolve and disappear. The acid solution is separated from the ether by a separating funnel, filtered, if necessary, and evaporated over a water bath, when the action represented by the following equation takes place C H NHC H OOCC H HCl (Benzoylmono-ethyl-mydriatin hydrochlorid=al1ocain A) phenyl-amino-alcohols either of higher or lower homologues of mydriatin, and benzoyl derivatives of monoand di-alkyl or alkaryl derivatives of those phenylaminoalcohols possess more or less anethetic properties. However, others have no special advantage when compared with the two allocain compounds in question which can be produced with minimum expense and in a simple manner.

/Vhat I claim is: 1. As a new compound, an organic acid ester of a mydriatin derivative, said compound having probably the formula where is an organic acid radical; X is hydrogen, or an'alkaryl group; and X is an alkaryl group.

2. As a new compound, a benzoylethylmydriatin.

3. As a new compound, benzoylmono-ethylmydriatin, having probably the formula 4L. A. new composition of matter comprising a mixture of benzoyl mono-ethyland diethylmydriatin. Y

In testimony whereof, I afiix my signature.

NAGAYOSHI NAGAI.

The turbid solution is filtered, 

